In a study reported in Alzheimer’s & Dementia, scientists have identified specific ways that key blood vessel growth genes behave differently in various types of brain cells in people with Alzheimer’s disease, pointing to potential new treatment approaches.
Timothy Hohman, PhD, professor of Neurology at Vanderbilt University Medical Center, and his group build here on previous work on these genes, known as vascular endothelial growth factors (VEGF). Their earlier research examining postmortem brain tissue samples found that expression levels of several of these genes were associated with how quickly cognition declined in Alzheimer’s disease and with the accumulation of harmful proteins in the brain.

“Our previous work showed these genes were important in Alzheimer’s disease, but we needed to understand exactly which brain cell types were involved,” Hohman said. “A pilot analysis of a small single-cell transcriptome dataset gave us some initial clues, but we needed to look at a much larger group of individuals to confirm and expand those findings.”
In this new study, the team analyzed brain tissue from 424 deceased donors who had participated in long-term studies of aging and memory. Examining gene expression cell by cell, they focused on a family of 10 genes involved in blood vessel development.
“We know that the same gene can have different associations with Alzheimer’s pathology depending on which brain cell type is expressing it,” Hohman said. “This underscores the importance of examining gene effects at the level of individual cell types.”
The researchers discovered that expression levels of one gene, called FLT1, are higher in both blood vessel cells and immune cells in the brains of people with Alzheimer’s disease. More specifically, in both these cell types, higher expression of FLT1 was associated with worse cognitive performance. And higher expression of FLT1 in immune cells was associated with higher levels of a protein called amyloid beta, considered a hallmark of Alzheimer’s disease pathology.

“This makes FLT1 an intriguing potential therapeutic target,” said lead author Yiyang Wu, MD, PhD, associate data scientist with the Vanderbilt Memory & Alzheimer’s Center. “However, since we see altered expression of this gene in more than one cell type in Alzheimer’s disease, we need to understand how targeting FLT1 might affect these different cell populations in the brain.”
The study also revealed that another gene, VEGFB, shows opposing effects in different cell types. In nerve cells that inhibit brain activity, higher expression of VEGFB was linked to lower levels of amyloid beta accumulation. However, in oligodendrocytes, support cells that insulate nerve fibers, higher VEGFB expression was associated with higher levels of amyloid beta.
The research took advantage of a technology called single-cell RNA sequencing, which allowed the team to analyze around 3,800 individual cells from each person’s brain tissue. This provided an unprecedented level of detail about VEGF family gene expression in specific cell types.
“Understanding these cell-specific expression patterns gives us important new insights,” Hohman said. “Our findings suggest that the relationship between these genes and Alzheimer’s disease is more complex than previously thought, with different patterns emerging in different brain cell types.”
The researchers also found that the typical communication patterns between cells involving these genes were significantly altered in Alzheimer’s disease, with overall communication through these signaling pathways reduced in people with Alzheimer’s compared to those with normal cognition. However, one specific signaling pathway remained strong in Alzheimer’s, suggesting it might play a role in the disease process, that is, the communication led by VEGFA and FLT1 protein sent from support cells called astrocytes to blood vessel cells.
The research was conducted using brain tissue and gene expression data from the Religious Orders Study and the Rush Memory and Aging Project, two long-term studies of aging and memory loss.
Others from VUMC on the study include Julia Libby and Logan Dumitrescu, PhD. They were joined by researchers from Columbia University in New York City and Rush University in Chicago. The study was supported by the National Institutes of Health (grants P30AG010161, P30AG072975, R01AG015819, R01AG017917, U01AG046152, U01AG061356, R01AG061518, R01AG074012, R01AG059716).